This project will focus on novel interactions between breast cancer cells and tumor associated macrophages that contribute to increased tumor malignancy. Our previous studies have defined an EGFR/CSF1R paracrine loop operating between these two cell types and its role in invasion and intravasation. In this proposal we will evaluate additional novel interactions between tumor cells and macrophages which could be critical for patient survival. We propose that neuregulins and CXCR2 ligands secreted by tumor cells activate ErbB3 and CXCR2 on macrophages, resulting in increased production of AREG, HBEGF and angiogenic factors by macrophages. HBEGF and AREG simulate tumor cell invasiveness, while the angiogenic factors disrupt the endothelial barrier, with the combined results leading to increased intravasafion. We propose three specific aims in which we will test these hypotheses. In Aim 1 we will evaluate the role of stimulation of macrophage ErbB3 by neuregulins secreted by tumor cells. In Aim 2 we will evaluate the role of macrophage CXCR2. In Aim 3, we will examine the roles of HBEGF, AREG and angiogenic factors produced by macrophages. The project will integrate the use of in vitro and in vivo models of intravasation and extravasation provided by Cores A, B, and C to study the role of these pathways in breast cancer metastasis. Close collaboration with the other projects in the PPG will facilitate evaluation of macrophage polarizafion and dynamics during invasion and metastasis (Project 1), mechanisms of CSFl R synergy with ErbBS and GPCR signaling (Projects 2 and 4), and the roles played by the ErbB3/CXCR2 pathways contributing to the various steps in transendothelial migration (Project 5). The ultimate goal is to identify new options for prognosis and therapeutic interventions.